Opioid modulation of neural encoding of motivation and reward

描述（由申请人提供）：我们的长期目标是了解神经奖励回路在正常消费和包括暴饮暴食的病理中控制食物摄入的作用。我们特别感兴趣的是奖励回路中的阿片信号，特别是在伏隔核（sNAcc）的外壳中，是如何介导暴饮暴食的。在饮食诱导的暴饮暴食大鼠模型中，刺激sNAcc中的mu阿片受体（MORs）诱导贪食，sNAcc阿片受体和配体表达发生改变。然而，sNAcc MOR刺激导致暴饮暴食的机制，以及饮食诱导的该回路的变化如何导致暴饮暴食行为，仍然知之甚少。在之前的研究中，我们描述了sNAcc神经元的两种放电模式，我们假设它们在味觉享乐的加工和食欲寻找行为的控制中起着重要而独特的作用。我们的数据表明，第一种激发模式编码了适口性，而第二种激发模式通过一种去抑制机制，允许地控制寻找食物的行为（以及随后的消费）。在本研究中，我们将验证sNAcc MOR刺激对这些放电模式的不同影响，通过分离的解剖通路中的信号传导来增加可口性诱导的贪食和寻找食物的食欲行为。我们进一步假设，饮食引起的暴饮暴食是通过介导食欲性食物寻找的神经通路中阿片信号的敏化而产生的，而不是通过处理适口性的通路的变化。为了解决这些假设，我们将结合体内电生理和药理学方法来表征sNAcc MOR操作对sNAcc传出靶点放电的影响。我们将使用同步电极阵列记录和相互关联技术来研究sNAcc和目标区域之间的相互作用，以表征这些区域之间的功能连通性。最后，我们将在饮食诱导暴饮暴食的大鼠模型中描述该回路发生的电生理和药理学变化。我们预计这些实验将为sNAcc MOR刺激和饮食诱导暴饮暴食引起的暴饮暴食的机制提供重要的见解。这些实验将导致对强迫性食物摄入背后的神经回路机制有更深入的了解，因此与开发针对神经性贪食症等饮食失调的新型治疗干预措施高度相关。

DESCRIPTION (provided by applicant): Our long-term goal is to understand the contribution of neural reward circuits to control of food intake during normal consumption as well as in pathologies that incorporate binge eating. We are specifically interested in how opioid signaling within reward circuits, particularly in the shell of the nucleus accumbens (sNAcc), mediates binge-like food intake. Stimulation of mu opioid receptors (MORs) in the sNAcc induces voracious feeding and sNAcc opioid receptor and ligand expression is altered in rat models of diet-induced binge eating. However, the mechanisms through which sNAcc MOR stimulation causes hyperphagia, and how diet-induced changes in this circuit contribute to binge eating behavior, remain poorly understood. In previous studies, we characterized two firing patterns in sNAcc neurons that we hypothesize play important and distinct roles in processing of taste hedonics and controlling appetitive food-seeking behavior. Our data suggests that the first of these firing patterns encodes palatability, while the second serves to permissively gate food-seeking behavior (and subsequent consumption) through a disinhibition mechanism. In the present proposal, we will test the hypothesis that distinct effects of sNAcc MOR stimulation on these firing patterns act to increase palatability-induced hyperphagia and food-seeking appetitive behaviors through signaling in segregated anatomical pathways. We further hypothesize that diet-induced binge eating arises specifically through sensitization of opioid signaling in the neural pathway mediating appetitive food-seeking, rather than through changes in pathways processing palatability. To address these hypotheses, we will use a combination of in vivo electrophysiological and pharmacological approaches to characterize the effects of sNAcc MOR manipulations on firing in efferent targets of the sNAcc. We will investigate interactions between the sNAcc and target regions using simultaneous electrode array recordings and cross-correlation techniques to characterize functional connectivity between these regions. Finally, we will characterize electrophysiological and pharmacological changes occurring in this circuit in a rat model of diet-induced binge eating. We anticipate that these experiments will provide important insights into the mechanisms underlying hyperphagia caused by sNAcc MOR stimulation and diet-induced binge eating. These experiments will lead to greater understanding of neural-circuit mechanisms underlying compulsive food intake, and are thus highly relevant in developing novel therapeutic interventions for eating disorders such as bulimia nervosa.